Morpholine, 4-[(triethoxysilyl)methyl]-

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2007-06-06 to 2007-11-28

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD test under GLP

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2007

Report date:

2007

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

July 27, 1995

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

480-370-1

EC Name:

-

Cas Number:

21743-27-1

Molecular formula:

Hill formula: C11H25NO4Si CAS formula: C11H25NO4Si

IUPAC Name:

4-[(triethoxysilyl)methyl]morpholine

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann GmbH, D-33178 Borchen
- Age at study initiation: 6-8 weeks
- Weight at study initiation: males: 186 - 209 g , females: 150 - 180 g
- Housing: semi barrier in an air conditioned room
- Diet (e.g. ad libitum): at libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: adequate

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 55 +/- 10%
- Air changes (per hr): 10/h
- Photoperiod (hrs dark / hrs light): 12 h dark, 12 h light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Justification for use and choice of vehicle (if other than water): the vehicle was chosen due to its non-toxic characteristics.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Does verification was performed by quantification of the test item using AAS. The fortification level covered approximately 20, 150 and 1000 mg test item/ 5 ml corn oil.

Duration of treatment / exposure:

Test duration: 28 days

Frequency of treatment:

Dosing regime: 7 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 20, 150, 1000 mg/kg bw/day (m/f)
Basis:
actual ingested

No. of animals per sex per dose:

Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 20 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 5 animals at 1000 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 20 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 5 animals at 1000 mg/kg bw/day

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Preliminary Test
- Post-exposure recovery period in satellite groups: none

Positive control:

No positive control was used.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes, twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first exposure and in the final week in all animals with specific emphasis on locomotion and behaviour.

BODY WEIGHT: The animals were weighed prior to first application (day 0) and once a week thereafter (day 7, 14, 21, 27)

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: day of necropsy
- Anaesthetic used for blood collection: Yes (not stated in the report)
- Animals fasted: Yes
- How many animals: all

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day of necropsy
- Animals fasted: Yes
- How many animals: all

URINALYSIS: Yes
- Time schedule for collection of urine: day of necropsy
- Metabolism cages used for collection of urine: No
- Animals fasted: Yes

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations:Once before the first exposure and in the fourth exposure week.
- Dose groups that were examined: 0, 20, 150, 1000 mg/kg bw/day
- Battery of functions tested: sensory activity / grip strength / motor activity

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
All animals in the study were subjected to a full, detailed gross necropsy which included careful examination of the external surface of the body, all orifices and the cranial, thoracic and abdominal cavaties and their contents.

HISTOPATHOLOGY: Yes
Full histopathology was carried out on the preserved organs and tissues of all animals in the Control (0 mg/kg bw/day) and High Dose (1000 mg/kg bw/day) groups.

Statistics:

For statistical analysis one-way analysis of variance (ANOVA) was carried out, followed by Student's t-test to reveal any differneces between control- and test groups.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Clinical observations:
No mortality occurred during the study period.
The mean body weight development in all male dose groups was
almost unaffected when compared to the standard growth curve
for this strain. Females showed higher weight gain to the
corresponding control group, reaching statistically
significance at 1000 mg/kg bw/d. Food consumption was found
slightly, but statistically significant, reduced for all
female dose groups compared to the corresponding controls.
No differences were observed concerning functional and
behavioural examination prior to application and during the
last week of dosing, respectively. Responses to reflex
testing were normal in all groups.

Laboratory findings:
The values for haematology were in normal ranges without
significant deviations.
For a small number of clinical biochemistry parameters the
differences between control and test groups attained a
degree of statistical significance. However, these
differences were all within the range of the historical
control data for this rat strain, so no toxicological
significance was attached to these findings.
No test substance-related differences in urinalysis
parameters were noted when compared with the control values.

Effects in organs:
There were no changes in organ weights, macroscopic and
microscopic examination that were considered to be an effect
of treatment.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: original NCD unit is mg/kg/day.

2

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: original NCD unit is mg/kg/day.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The test item has not to be classified according to EU criteria. The NOAEL and the NOEL as identified by this study were 1000 mg/kg bw/day.

Executive summary:

In a 28 days oral administration test with the test item N-(Morpholinomethyl)triethoxysilane groups of 5 male and female rats (HsdRccHan : WIST) were exposed to 0, 20, 150 and 1000 mg/kg bw/day by gavage with corn oil as the vehicle. No mortality occurred during the study period. The mean body weight development in all male dose groups was almost unaffected when compared to the standard growth curve for this strain. Females showed higher weight gain to the corresponding control group, reaching statistically significance at 1000 mg/kg bw/d. Food consumption was found slightly, but statistically significant, reduced for all female dose groups compared to the corresponding controls. No differences were observed concerning functional and behavioural examination prior to application and during the last week of dosing, respectively. Responses to reflex testing were normal in all groups. The values for haematology were in normal ranges without significant deviations. For a small number of clinical biochemistry parameters the differences between control and test groups attained a degree of statistical significance. However, these differences were all within the range of the historical control data for this rat strain, so no toxicological significance was attached to these findings. No test substance-related differences in urinalysis parameters were noted when compared with the control values. There were no changes in organ weights, macroscopic and microscopic examination that were considered to be an effect of treatment. Based on the results of the study, 1000 mg/kg bw/day is considered to be the no-observed-adverse-effect-level (NOAEL) and the no-observed-effect-level (NOEL) for the test substance in animals of both sexes.